1. Field of Invention
This invention relates to a process for forming medical implants of cross-linked ultrahigh molecular weight polyethylene having an improved balance of wear properties and oxidation resistance.
2. Description of Related Art
It is known in the art that ultrahigh molecular weight polyethylene (UHMWPE) can be cross-linked by irradiation with high energy radiation, for example gamma radiation, in an inert atmosphere or vacuum. Exposure of UHMWPE to gamma irradiation induces a number of free-radical reactions in the polymer. One of these is cross-linking. This cross-linking creates a 3-dimensional network in the polymer which renders it more resistant to adhesive wear in multiple directions. The free radicals formed upon irradiation of UHMWPE can also participate in oxidation which reduces the molecular weight of the polymer via chain scission, leading to degradation of physical properties, embrittlement and a significant increase in wear rate. The free radicals are very long-lived (greater than eight years), so that oxidation continues over a very long period of time resulting in as much as a 5-fold increase in the wear rate as a result of oxidation over a period of about 5 years. As such, the wear rate of traditionally irradiated materials is significantly greater than unirradiated materials.
Sun et al. U.S. Pat. No. 5,414,049, which patent is hereby incorporated by reference, discloses a process for improving the oxidation resistance of medical implants which have been sterilized with radiation. In a preferred embodiment, a raw polymeric material is obtained by forming a virgin resin powder from which air and moisture have been removed prior to the forming process. The forming process, e.g. ram extrusion or compression molding of the powder is also preferably carried out in an inert low oxygen atmosphere. A medical implant is formed from the raw material, e.g an olefinic material such as UHMWPE, and is sealed in an oxygen impermeable package in an oxygen reduced non-reactive atmosphere and radiation sterilized, followed by heating the sterilized packaged implant at a temperature of between 37xc2x0 C. and the melting point of the olefinic material. The heating step forms cross-links between remaining free radicals formed during the radiation sterilization step, thus improving the oxidation resistance of the material. If the annealing temperature is too high, the thermal treatment can cause distortion of the UHMWPE implant, which is undesirable in orthopedic end-uses where the implants are generally machined or molded to close tolerances. If the temperature profile during annealing is adjusted to lower temperatures to avoid distortion of UHMWPE implants, incomplete extinguishing of the free radicals generally occurs and the UHMWPE oxidizes upon exposure to air or moisture.
Hyun et al. published International Application WO 96/09330, which application is hereby incorporated by reference, discloses a process for forming oriented UHMWPE materials for use in artificial joints by irradiating with low doses of high-energy radiation in an inert gas or vacuum to cross-link the material to a low degree, heating the irradiated material to a temperature at which compressive deformation is possible, preferably to a temperature near the melting point or higher, and performing compressive deformation followed by cooling and solidifying the material. The oriented UHMWPE materials have improved wear resistance. Medical implants may be machined from the oriented materials or molded directly during the compressive deformation step. The anisotropic nature of the oriented materials may render them susceptible to deformation after machining into implants.
Salovey et al. published European Application EP 722973, which application is hereby incorporated by reference, discloses a method for enhancing the wear-resistance of polymers, including UHMWPE, by crosslinking them via irradiation in the melt or using peroxide or similar chemical agents.
The process of the present invention eliminates the problem of thermal distortion of the implant by irradiating and thermally treating a consolidated UHMWPE material prior to forming an implant therefrom. By separating the irradiation cross-linking step from the sterilization step, the current invention allows one to use lower levels of irradiation for cross-linking than would be effective for sterilization of UHMWPE. Additionally, the heat treatment step following irradiation may be performed at temperatures near or above the melting point, which would distort the shape of a machined or molded implant which has been packaged for final sterilization. Heat treatment near or above the melting point results in improved molecular mobility, elimination of free radicals in the crystalline regions of the polymer which cannot occur at temperatures below the melt, and increased cross-linking and reduced oxidation in aged samples. When heat treatment is carried out at lower temperatures, incomplete quenching of free radicals results in residual oxidation upon aging. By separating the irradiating and annealing steps, the process of the current invention also avoids the need to irradiate in the melt, which is difficult to achieve on a commercial scale. An additional object of the current invention is to prepare a medical implant of cross-linked UHMWPE having improved wear properties without the use of chemical cross-linking agents. Medical implants formed from the cross-linked UHMWPE material of the current invention may be packaged in an air-permeable package and sterilized using non-irradiative methods such as gas plasma or ethylene oxide, eliminating the need to package the implants in an inert atmosphere. The cross-linked UHMWPE of the current invention can also be used in nonmedical applications requiring high wear resistance.
The current invention pertains to a process for preparing cross-linked ultrahigh molecular weight polyethylene useful in medical implants. The process involves irradiating a preform of ultrahigh molecular weight polyethylene, preferably with gamma radiation. Optionally, the preform may be annealed prior to irradiation in an inert atmosphere without the application of external pressure. The irradiated preform is then annealed in a substantially oxygen free atmosphere at a temperature at or above the onset of melting temperature, preferably near or above the peak DSC melting point, for a sufficient time to substantially recombine (eliminate) all the free radicals and crosslink the ultrahigh molecular weight polyethylene. This annealing step may be done under isostatic or hydrostatic pressure. The annealed preform is cooled while maintaining the oxygen free atmosphere and formed into a medical implant. The implant is sterilized using non-irradiative methods. Sterilization preferably is done by packaging the implant in an air permeable package and treating with gas plasma.
The invention further pertains to an improved cross-linked ultrahigh molecular weight polyethylene that can be made by the process of this invention. This cross-linked ultrahigh molecular weight polyethylene preferably has a swell ratio of less than about 5 and oxidation level of less than about 0.2 carbonyl area/mil sample thickness after aging under an oxygen pressure of about 5 atmospheres. It preferably has a percent elongation at break of at least 250, a single notch IZOD strength of at least 15 foot pounds per inch (ft lb/in) of notch, and a double notch IZOD strength of at least 35 ft lb/sq. in. The medical implant of this cross-linked ultrahigh molecular weight polyethylene exhibits an improved balance of wear properties and oxidation resistance. Wear properties are superior to those of conventional ultrahigh molecular weight polyethylene sterilized using gas plasma or gamma-irradiation. Oxidative resistance is significantly improved over conventional gamma-sterilized ultrahigh molecular weight polyethylene and is comparable to unirradiated, gas plasma sterilized ultrahigh molecular weight polyethylene.
For the purposes of this invention ultrahigh molecular weight polyethylene is defined as a polyethylene having an estimated weight average molecular weight in excess of about 400,000, usually 1,000,000 to 10,000,000 as defined by a melt index (ASTM D-1238) of essentially zero and a reduced specific viscosity greater than 8, preferably 25-30.
An UHMWPE preform is used as the starting material in the current process. The term preform is used herein to refer to a shaped article which has been consolidated, such as by ram extrusion or compression molding of UHMWPE resin particles into rods, sheets, blocks, slabs or the like. Such preforms may be obtained or machined from commercially available UHMWPE, for example GUR 4150 HP ram extruded UHMWPE rods from PolyHi Solidur (Fort Wayne, Ind.). The starting preform may also be pressure recrystallized as described in Howard U.S. Pat. No. 5,478,906, which patent is hereby incorporated by reference. The UHMWPE preform material does not contain stabilizers, antioxidants, or other chemical additives which may have potential adverse effects in medical applications.
The process of the current invention includes the steps of irradiating a UHMWPE preform to form free radicals and cross-link the UHMWPE, annealing the irradiated UHMWPE preform at elevated temperature in a substantially oxygen free atmosphere to eliminate any free radicals remaining from the irradiation step, thus further cross-linking and increasing the oxidation resistance of the irradiated UHMWPE, and forming a medical implant from the annealed cross-linked preform. Gamma radiation is preferably used in the irradiation step, however electron beam or x-ray radiation may also be used. Ultrahigh molecular weight polyethylene prepared according to the process of the current invention has an improved balance of wear properties and oxidation resistance. The increased cross-linking results in reduced swell ratios, generally less than about 5, and improved wear performance with comparable oxidation resistance relative to unirradiated UHMWPE.
The preform is preferably irradiated in the solid state with gamma radiation at a dose of about 0.5-10 Mrad using methods known in the art. Preferably, the preform is irradiated at a dose of about 1.5-6 Mrad. Radiation doses of less than about 0.5 Mrad generally provide insufficient cross-linking to provide the desired increase in wear properties in the final implant. While doses of greater than 10 Mrad may be used, generally the additional improvement in wear properties that is achieved by the higher dose is offset by increasing brittleness of the UHMWPE due to higher levels of cross-linking. Ultrahigh molecular weight polyethylene prepared using the process of the current invention generally has a percent elongation at break of at least about 250, single notch Izod strength of at least about 15 ft lb/in of notch, preferably at least about 17 ft lb/in of notch, and double notch Izod strength of at least about 35 ft lb/sq in. UHMWPE which has been pre-annealed or annealed at temperatures greater than about 280xc2x0 C. generally have a percent elongation at break of at least about 400, preferably at least about 500. The irradiation step is generally performed at room temperature, however higher temperatures may be used.
The preform is optionally contained in an inert atmosphere or vacuum, such as in an oxygen impermeable package during the irradiation step. Inert gases such as nitrogen, argon, and helium may be used. If a vacuum is used, the packaged material may be subjected to one or more cycles of flushing with an inert gas and applying a vacuum to eliminate oxygen from the package. Examples of packaging materials include metal foil pouches such as aluminum or MYLAR(copyright) polyester coated packaging foil which is available commercially for heat-sealed vacuum packaging. Polymeric packaging materials such as polyethylene terephthalate and poly(ethylene vinyl alcohol), both of which are commercially available may also be used. Irradiating the preform in an inert atmosphere reduces the effect of oxidation and accompanying chain scission reactions which can occur during gamma-irradiation. Oxidation that is caused by oxygen which is present in the atmosphere during irradiation is generally limited to the surface of the preform. Since the process of the current invention radiation cross-links the UHMWPE prior to forming the implant, low levels of surface oxidation can be tolerated as the oxidized surface can be removed during subsequent machining of the implant from the preform.
After the UHMWPE preform has been gamma irradiated, it is heat treated by holding at elevated temperature in a substantially oxygen-free atmosphere, typically created by introducing inert gas or employing a vacuum, for a time that is sufficient to recombine substantially all of the free-radicals which remain in the material from the irradiation cross-linking step, thus further cross-linking the material and stabilizing it to oxidation. Thermal distortion of the preform material during heat treatment may occur without affecting the final implant since the implant is formed from the preform after heat treatment. This allows higher temperatures to be used than would be possible in processes where the finished implants are heat treated. The hold time required for reaction of the free radicals decreases with increasing temperature. Thus, a wide range of temperatures, including temperatures above the melting point of the UHMWPE, is acceptable in the heat treatment step of the current invention.
The irradiated preform preferably is heated at a temperature at or above the onset of melting temperature of the irradiated heat-treated preform material, and preferably at a temperature near or above the peak melting temperature of the irradiated heat-treated polymer for a time of 2-120 hours, preferably 5-60 hours, more preferably 12-60 hours. The onset of melting temperature is defined herein as the temperature at the intersection of the baseline and steepest negative slope of the DSC melting endotherm. The baseline intersects the initial portion of the melting endotherm and is tangent to the final portion of the curve. The peak melting temperature is defined herein as the location of the peak of the melting endotherm. The onset of melting temperature for irradiated, heat-treated UHMWPE is generally about 120xc2x0 C. and the peak melting temperature is generally between 135xc2x0 C. and 140xc2x0 C. An especially preferred embodiment of the current invention is irradiation with a dose of 1.5-6 Mrads followed by heat treatment at 150-170xc2x0 C. for a period of 6-60 hours, more preferably 12-60 hours. The temperature and hold time that is sufficient to react substantially all of the free-radicals may be determined by measuring the oxidation of the samples using the method described below. Preferably, the temperature and hold time are chosen such that oxidation levels of less than about 0.2 carbonyl area/mil sample thickness, preferably less than about 0.1 carbonyl area/mil sample thickness, after aging as measured by this method are obtained. Heat treatment at or above the onset of melting temperature results in improved molecular mobility and elimination of free radicals in the crystalline regions of the polymer and increased cross-linking and reduced oxidation in aged samples. When heat treatment is carried out at lower temperatures, elimination of free radicals is less complete resulting in higher levels of residual oxidation upon aging.
Standard UHMWPE may be irradiated and pressure recrystallized to convert the UHMWPE into an extended chain conformation by conducting the heat treatment step using the temperatures and pressures disclosed for pressure recrystallization in U.S. Pat. No. 5,478,906. In pressure recrystallizing UHMWPE, the polymer is placed in a pressure vessel in water and enough pressure to withstand the pressure the water will develop at the operating temperatures. The temperature of the vessel is raised to melt the polyethylene which generally melts at 135-150xc2x0 C. at one atmosphere, and about 200xc2x0 C. at 50,000 psi. The time required to melt the polymer depends on the size of the UHMWPE preform used. Because UHMWPE is a poor heat conductor and has a very high heat of crystallization, it can take 1-2 hours to heat a 3 in. diameter rod to 200xc2x0 C. with the vessel at 220xc2x0 C. Once the polymer is hot and molten, the pressure is applied. Preferred pressures are about 33 kpsi (230 MPa) to 70 kpsi (480 MPa). Further improvement in properties may be achieved by annealing the UHMWPE in an inert atmosphere at temperatures above the melting point prior to pressure recrystallization. Pressures of greater than 45 kpsi (310 MPa) are preferred for pressure recrystallization of material which is pre-annealed prior to pressure recrystallization. The cooling time normally is about 6 hours from 250xc2x0 C. to 75xc2x0 C., but forced cooling of the vessel can reduce this to 1-2 hours with no adverse effects on the product.
Preferably, the UHMWPE material prepared according to the process of the current invention is an isotropic material, with no significant molecular or crystalline orientation. In order to prevent inducing residual stress in the polymer, thermal treatment after irradiation is preferably performed in such a manner that no non-uniform forces which could lead to deformation of the material during heat treatment will occur. During heat treatment the preform can be subjected to uniform pressure, such as isostatic or hydrostatic pressure, or alternatively, the preform can be heated in the absence of any externally applied pressure, so as to not deform the UHMWPE. It is undesirable to deform the preform by application of compressive or other forces as this results in an oriented material which may deform due to internal stresses after machining of the implant.
After a predetermined time, the cross-linked preform is cooled while still in an inert atmosphere or vacuum. The cross-linked preform is cooled to a temperature less than about 100xc2x0 C., preferably less than about 50xc2x0 C., more preferably to room temperature, prior to exposing the preform to air. If the preform was packaged during the heat treatment step, after cooling it is removed from the packaging and formed into an implant using methods known in the art such as machining. The cross-linked UHMWPE is especially useful as a bearing surface, for example in prosthetic hip joint cups and as other prosthetic shapes for replacement of other joints of the human body, including knees, shoulders, fingers, spine, and elbows. The finished implant is then packaged and sterilized using non-radical-forming methods. Because the implant is oxidatively stabilized, it is not necessary to package the finished implant in an inert atmosphere. For example, the implant can be packaged in air-permeable packaging and sterilized using gas plasma or ethylene oxide methods which are known in the art. For example a PLAZLYTE(copyright) gas plasma sterilization unit, manufactured by Abtox (Mundelein, Ill.), may be used.
In an alternate embodiment of the current invention, the UHMWPE preform is pre-annealed prior to the irradiation step. In the pre-annealing step, the preform is subjected to a temperature of 280xc2x0 C.-355xc2x0 C., preferably 320xc2x0 C.-355xc2x0 C., for at least 0.5 hour, preferably at least 3 hours, in an inert atmosphere, without the application of external pressure. It is generally desirable to heat the polymer as close as possible to, without reaching, its decomposition temperature. The pre-annealed preform is then cooled non-precipitously to a temperature of about 130xc2x0 C. or below, the rate of cooling being such that temperature gradients producing internal stresses in the article are substantially avoided. Rapid cooling, such as by immersion in cold water, should be avoided as it causes internal voids to form. It is generally convenient to allow the polymer to cool wrapped in insulation. The pre-annealed preform has improved elongation, impact resistance, and crystallinity over the starting UHMWPE. The cooled pre-annealed preform is then irradiated and annealed as described above.
Unless noted otherwise, test specimens were prepared from the interior of the preform rods.
Type IV tensile specimens comforming to ASTM D-638 were machined from the UHMWPE sample materials. The test specimens were mounted in a Lloyd LR10K mechanical test frame and tested for the tensile yield stress (TYS), ultimate tensile stress (UTS) and percent elongation according to ASTM D-638. Type IV specimens were used to measure UTS, TYS, and percent elongation for Examples 1-27, and Comparative Examples A-C.
Type I tensile specimens were machined from the UHMWPE samples and mounted in the test frame. Tensile modulus was measured on these samples according to ASTM D-638. Type I tensile specimens were also used to measure TYS, UTS and percent elongation for Examples 28-37 and Comparative Example D.
All tensile properties represent the average of 5 test specimens.
Thermal analysis was performed on disks approximately 3 mm thick and 1.5 mm in diameter which were cut from the UHMWPE sample rod. The disk was placed in a differential scanning calorimetry (DSC) sample pan and weighed. The lid was placed on the pan and crimped in place. The pan was placed in a DuPont Model 2000 thermal analyzer and allowed to equilibrate at a temperature of 50xc2x0 C. It was then heated at a rate of 20 degrees C./minute. The peak melting point was taken as the location of the peak of the melting endotherm. The onset of melting temperature was determined from the DSC curve as the intersection of the baseline and the steepest negative slope of the melting endotherm. The baseline intersects the initial portion of the melting endotherm and is tangent to the final portion of the curve. The heat of fusion (Hf) was calculated as the area of the melting endotherm.
The percent crystallinity was determined by dividing the measured heat of fusion by the theoretical heat of fusion of crystalline UHMWPE, 290 J/g.
Density measurements were performed on 1.5 mm thick disks of UHMWPE cut from the UHMWPE sample rods. The disks were soaked in a 65/35 solution by weight of 2-propanol, histological grade, and water. The sample was placed into a calibrated density gradient column. The density was determined from the equilibrium position of the sample in the column and is reported as g/cc.
Resistance to deformation (creep) was measured in accordance with ASTM D-621 with the following modifications: samples machined into cylinders or cubes without the use of lubricating liquids; samples measured 0.5 in.xc3x970.5 in.xc3x970.5 in.
Impact resistance was measured using the notched Izod test given in ASTM D-256 with the following modifications: samples machined into shape without the use of lubricating liquid; type A or notched IZOD; specimen size was 0.5 in.xc3x972.5 in.; 0.4 in. from bottom of vertex to opposite side; 1.25 in. impacted end (from end of bar to vertex of notch); the notch should be the specified angle of 22.5 degrees. Impact strength was also measured using double notched Izod specimens and the test method described in ASTM F-648 Annex A1.
Oxidative aging was performed on specimens which were wrapped in porous breather fabric to prevent close packing of the specimens and allow free gas access to all surfaces. The specimens were then loaded into a 4 in.xc3x978 in. cylindrical pressure bomb and sealed. The bomb was pressurized to 5 atmospheres (73.5 psi) with oxygen and heated with cylindrical band heaters to 70xc2x0 C. and held for 14 days. Aged wear test results were obtained by aging the hip cups using this procedure prior to wear testing. Similarly, aged Izod specimens for double notch impact strength measurements were prepared according to ASTMF-648 Annex A1 followed by oxidative aging prior to strength measurements.
Specimens for oxidation measurements were cut from the interior of the cooled preform rods after gamma-irradiation and annealing. The samples were 45 degree wedge cuts from 0.5 inch thick by 2.5 inch diameter disks. Oxidation measurements were made on 250 micron thick sections prepared by cutting the wedge-shaped specimens through their thickness using a band saw. A 250 micron thick slice was microtomed off the freshly exposed surface and analyzed using FTIR. Aged oxidation results were obtained from wedge cuts that were aged according to the oxidative aging procedure described above prior to preparing the 250 micron thick section. The sample was mounted in a Digilab FTIR fitted with a microscope with a motorized stage. The FTIR aperture was focused through the microscope to allow measurement of the infrared absorbance in a small (25 micronxc3x97200 micron) section of the sample. The microscope stage was moved by a stepper motor in increments of 50 microns to measure the carbonyl absorbance at a number of locations from the surface down to a depth of 4 mm. Oxidation was quantified based on the absorbance of the carbonyl peaks at 1670-1730 wavenumbers as compared to a reference peak corresponding to methylene stretching along the polymer backbone at 4250 wavenumber using the method of Nagy and Li, A Fourier Transform Infrared Technique For The Evaluation of Polyethylene Bearing Materials, Transactions, 16th Annual Meeting, The Society for Biomaterials, 3:109, 1990. An average oxidation level was calculated by integrating the carbonyl concentration versus depth curve to a depth of 2.05 mm. Oxidation is reported as carbonyl area/mil sample thickness.
Swell ratios were measured per ASTM D 2765 method C. The test specimens were 0.32 inch cubes. All swell ratios represent the average of 4 test specimens.
Gas plasma sterilization was performed by (a) placing the component in a breathable pouch and heat sealing, (b) placing the packaged components in the chamber of a PLAZLYTE(copyright) Sterilization System (Abtox, Inc., Mundelein, Ill.) and evacuating (c) filling the chamber with peracetic acid vapor and holding for a predetermined time, (d) evacuting the chamber, (e) filling the chamber with a filtered secondary plasma and holding for a predetermined time, (f) evacuating the chamber, (g) repeating steps (c)-(f), (h) filling the chamber with atmospheric air, (i) evacuating the chamber, and (j) repeating steps (h) and (i) to complete the cycle.
Wear rates were obtained by mounting test hip cups having a 28 mm spherical hole in the cup in a hip simulating wear tester which included 28 mm diameter femoral heads. The test cups were machined from the interior of the preform rods and were pre-soaked for 30 days in bovine calf serum solution containing 20 mM EDTA and 0.2 wt % sodium azide. The cups were sterilized by gas plasma prior to wear testing. The wear tester simulated the human gait using the Paul hip curve at a 1900 N peak load and a frequency of 1.1 Hz. The load is applied in the vertical direction. The test cup in the hip simulator is immersed in bovine calf serum and angled at 23 degrees from the horizontal. Every 500,000 cycles, the cups are washed, dried and weighed. Each test was run between 2.5 and 5 million cycles. Soak controls cups were used to correct for fluid absorption. The wear rate is the soak corrected change in cup weight per million cycles.